Case: A 27-year-old childless, single woman presented to CHR. Though concerned about her future fertility, she was not interested in conceiving at the time. She was of Middle-Eastern Mediterranean background, mildly obese with mostly truncal obesity (BMI 33). She also demonstrated moderate acne scars in her face and appeared mildly hirsute, with some dark facial hair and significant amounts of black hair on her arms.

She reported irregular menses since menarche at age 14, characterized by oligo-amenorrhea. Over the year prior to presentation to CHR, she claimed weight gain of ca. 15-20 lbs, without noticeable changes in exercise and/or eating habits. As a teenager, she was placed on OCPs to “regulate her period,” more for heavy menorrhagia episodes than menstrual irregularity. Her bleeding episodes were so severe that, twice as a teenager, she was admitted to a hospital and was treated for anemia.

With OCPs, her menstrual pattern regulated itself, and she stayed on birth control till age 24. Once she discontinued OCPs, she experienced six months of post-pill amenorrhea but then fell into a semi-regular menstrual pattern of 32-34 days, with a occasional amenorrheic months.

Her past medical history was otherwise insignificant except for an appendectomy at age 14, apparently without overt rupture. She had periodic visits with gynecologists and nurse midwifes over the years, though in irregular intervals. She was never advised of a diagnosis of polycystic ovary syndrome (PCOS). Her family history was also insignificant, except for the fact that her mother suffered from systemic lupus erythematosus (SLE).

Diagnostic work-up: A limited diagnostic work-up was ordered, which resulted in the following relevant results: The patient demonstrated hyper-androgenism, characterized by relatively high testosterone levels and relatively low sex hormone binding globulin (SHBG). Her DHEAS level was in mid-range. Her AMH level was high for her age at 7.4 ng/mL. In addition, the patient demonstrated FSH/LH inversion, a fairly typical finding with the “classical” PCOS phenotype. Her vaginal ultrasound examination demonstrated multi-cystic ovaries but not a typical “pearl-string” PCO-ovarian phenotype.

Her fasting glucose levels were in normal range, though her insulin levels were marginally elevated, suggesting early insulin resistance. The patient also demonstrated evidence of immune system activation with elevated total IgM and IgE levels and of inflammation, with abnormally high IL-6 and CRP. Her TSH was in clearly hypothyroid range and she demonstrated low level TPO as well as TG antibodies, leading to a diagnosis of likely Hashimoto’s thyroiditis.

Analysis: This patient’s work-up led to two distinct, yet often interwoven, diagnoses: She very clearly reflected the typical “classical” PCOS phenotype, characterized by truncal obesity, hyper-androgenism, a history of oligo-amenorrhea, hirsutism, elevated AMH levels, FSH/LH inversion and early insulin resistance. She, however, did not demonstrate a typical ovarian PCO-phenotype. In addition, she suffered from overt hypothyroidism and, based on evidence of thyroid autoimmunity, from Hashimoto’s thyroiditis. A hyperactive immune system was also confirmed by IgM and IgE gammopathies and elevated inflammatory markers in IL-6 and CRP.

PCOS is a widely misunderstood condition; it is perceived by many as “a disease,” which it is not. PCOS really is a group of separate conditions, which for reasons we will address below in more detail, have historically been thrown together in the medical literature in one “syndrome” named PCOS. Over the years, it has become apparent that this syndrome consists of very different patient groups, and groups of experts have tried to divide PCOS into distinct “phenotypes.”

This has, however, been only partially successful, as “experts” have not been able to agree on how this PCOS pie should be divided into individual phenotypes. Therefore, no consensus exists and different classifications of PCOS phenotypes are used in the medical literature, resulting in confusion and limited ability to compare results reported in various studies because investigated patient populations do not match.

Here discussed case represents the “classical” PCOS phenotype, except for the lack of the typical ovarian PCO phenotype on ultrasound. Many erroneously consider the “classical” PCOS to be the most frequent and most “typical” PCOS phenotype. That is not really the case. The literature suggests that the “classical” PCOS phenotype represents only ca. 40% of all PCOS patients. Indeed, an approximately equal number of PCOS patients (under most current international criteria) are lean women, without evidence of obesity, hirsutism, acne and the metabolic syndrome, which is so frequently found later in life in women with the “classical” phenotype.

Recent research at CHR that concentrated exclusively on this lean PCOS phenotype strongly suggests that etiologies and pathophysiologies of these two most frequent PCOS phenotypes, likely, are very different. Whether it makes sense to keep them within one syndrome and under one diagnostic parapet, therefore, has to be questioned.

Also widely underappreciated is the fact that PCOS is not necessarily a static condition. It, in principle, is a condition of young women and lightens in its reproductive clinical expression as women grow older. This, however, is not the case in the “classical” PCOS phenotype when it comes to the expression of signs and symptoms of the metabolic syndrome, which actually increase with advancing age.

Resolution: The patient was advised of her diagnoses, and was started on thyroid supplementation. She was also advised of her risks of developing the metabolic syndrome and of benefits of proper diet, exercise and weight control.

Because at least the “classical” PCOS phenotype is increasingly viewed as an inflammatory condition and because the patient demonstrated early signs of insulin resistance, she was also advised of anti-inflammatory and hypo-glycemic effects of Metformin but chose not to initiate treatment at the time. She, however, did start with a baby aspirin daily. PCOS has also been associated with increased risk toward autoimmunity, and especially thyroid autoimmunity. Here observed combination of diagnoses is, therefore, not unusual.

Regarding her future fertility, she was advised that her current ovarian reserve was normal, with her functional ovarian reserve, based on her high AMH, even being abnormally high. Any infertility treatment would, therefore, likely be successful but place her at some risks for ovarian hyper-stimulation as well as multiple pregnancy.

She also was advised that autoimmune thyroid disease (and other autoimmune conditions) statistically denote increased risk of premature ovarian aging (POA), which would be reflected in relatively quick declines in AMH values. She, therefore, was advised to undergo repeat AMH evaluations every 1-2 years. Finally, she was advised that, as a “classical” PCOS patient, she likely, was oligo-ovulatory, which meant that she may require help to conceive. Consequently, she should seek out help from a fertility expert if she did not conceive within 6 months with regular intercourse, and, if possible, should accelerate her pregnancy attempts.

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